Loss of ARHGAP40 in Breast Cancer by Hypermethylation and itsClinical Significance

Objective: ARHGAP40 is a Rho GTPase-activating protein (RhoGAP). The expression and biological roles of ARHGAP40 in breast cancer are unknown. We aimed to investigate the expression of ARHGAP40 and its epigenetic mechanism in breast cancer. Methods: The expression level of ARHGAP40 was examined in breast cancer cell lines and tissues. The methylation status of ARHGAP40 was analyzed using a bisulfite sequencing PCR (BSP). The biological roles of ARHGAP40 in breast cancer were investigated. Results: ARHGAP40 mRNA was significantly expressed in MCF-7 and weakly in MDA-MB-231, whereas methylated ARHGAP40 was detected in MDA-MB-231 and partly in MCF-7. ARHGAP40 protein was positively expressed in normal breast epithelial cells in all paracancerous tissues. The expression level of ARHGAP40 was significantly associated with age, TNM stage, lymph node metastasis, molecular subtypes, proliferative marker Ki67, and HER2 expression. The overall survival (OS) of patients with high expression of ARHGAP40 was longer than those with low expression. Overexpression of ARHGAP40 in MCF-7 and MDA-MB-231 cells induced apoptosis and suppressed cell proliferation. The opposite outcomes were observed in the ARHGAP40 knockdown experiment. Conclusion: Our data suggested ARHGAP40 to be downregulated in breast cancer due to hypermethylation. ARHGAP40 was found to act as a tumor suppressor in breast cancer and could be a potential therapeutic target for breast cancer.